Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion

Nat Genet. 2013 Feb;45(2):197-201. doi: 10.1038/ng.2507. Epub 2012 Dec 23.

Abstract

Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amidine-Lyases / genetics
  • Cytoskeletal Proteins
  • Death Domain Receptor Signaling Adaptor Proteins / genetics
  • Exome / genetics*
  • Fasting / blood
  • Finland
  • Gene Frequency
  • Genetic Variation*
  • Genetics, Population
  • Genotype
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Insulin / genetics*
  • Insulin / metabolism*
  • Insulin Secretion
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Mixed Function Oxygenases / genetics
  • Molecular Sequence Annotation
  • Proinsulin / blood
  • Tumor Suppressor Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Guanine Nucleotide Exchange Factors
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • KANK1 protein, human
  • MADD protein, human
  • SGSM2 protein, human
  • Tumor Suppressor Proteins
  • Proinsulin
  • Mixed Function Oxygenases
  • PAM protein, human
  • Amidine-Lyases